Figure 1. The EU1794 series of NMDAR NAMs can be converted to PAMs with subtle structural modifications.

(A) Representative concentration-response experiments for a negative (EU1794-2, above) and positive (EU1794-5, below) allosteric modulator using two-electrode voltage-clamp recordings of GluN1/GluN2D NMDARs activated by saturating concentrations of agonist. 100/30 µM glutamate/glycine application is represented by the grey bar and increasing concentrations of modulator are shown by grey scale boxes (0.3, 1, 3, 10, 30 µM for EU1794-2 and 1, 3, 10, 30, 100 µM for EU1794-5). (B) Chemical structures of the NAMs EU1794-2, EU1794-4, EU1794-19 and PAM EU1794-5 are given, which show all permutations of two methyl substitutions. This series illustrates how subtle changes in chemical structure interconvert modulator activity. (C) The concentration-response curves for the compounds shown in (B) acting on GluN1/GluN2D NMDARs activated by maximally effective concentrations of co-agonists and fitted by the Hill equation. (D) Chemical structures of EU1794 PAMs. (E) Concentration-response curves for EU1794 PAMs on the responses of GluN1/GluN2D NMDARs to maximally effective concentrations of co-agonists. See Table 1 for fitted EC₅₀ values at all diheteromeric NMDARs. Data represent 4–18 oocytes recorded in at least two independent experiments.